The main objective of this project is to identify genes contributing to human variation in heart rate variability (HRV), a noninvasive index of cardiac parasympathetic tone. Eight key genes involved in biosynthesis, transport, breakdown and receptor binding of acetylcholine will be assessed by a gene-wide approach with all variants within a candidate gene considered jointly. Making optimal use of the recently enlarged public databases of genetic variants in human populations, such an approach, best achieved through selection of a minimal set of tagging SNPs, affords gene-based replication and offers a promising solution to the lack of replicability of association studies. We will use the data from the Georgia Cardiovascular Twin Study, a cohort of 982 twin subjects including roughly equal numbers of black (219 pairs) and white American (272 pairs) youth and young adults who had beat-to-beat heart rate measured both at rest and during three acute behavioral stress tasks. We plan to calculate all the commonly used time and frequency-domain parameters of HRV by using freely available dedicated HRV software. In context of recent evidence suggesting that the effect of genes influencing HRV at rest may be more pronounced under behavioral stress, our twin design incorporating both HRV at rest and under stress, will enable us to define the most heritable phenotype for gene finding. The specific aims of this project are to test the hypotheses that: (1) genetic influence on HRV will increase during exposure to behavioral stress caused by a larger effect of the same genes that also underlie HRV at rest, and (2) variants in 8 key genes involved in the parasympathetic pathway will explain a significant part of the heritability of HRV. The long term objective of this project is to understand the genetic basis of cardiac autonomic function. Findings may lead to a more accurate prediction of individuals at risk and improve the effectiveness of primary interventions and contribute to the development of individualized therapy for cardiovascular disease (pharmacogenetics). Lay summary: Heart rate variability (HRV) measuring the beat-to-beat heart rate fluctuations over time is an indicator of cardiovascular health. Low HRV increases the risk of cardiovascular disease. We will look for variants in the genes involved in the regulation of HRV to see if they explain individual differences in HRV observed in the population. [unreadable] [unreadable] [unreadable]